The relationship between naevus count, memory function and telomere length in the Twins UK cohort

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The relationship between naevus count,

memory function and telomere length in the

Twins UK cohort

Stefano Masi | Georgios Georgiopoulos |

Simone Ribero | Stefano Taddei | Veronique Bataille |

Claire J. Steves

Submit your next paper to PCMR online at

http://mc.manuscriptcentral.com/pcmr

DOI: 10.1111/pcmr.12722

720  

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Received: 8 February 2018 

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S H O R T C O M M U N I C A T I O N

The relationship between naevus count, memory function and

telomere length in the Twins UK cohort

Stefano Masi

_{*  | Georgios Georgiopoulos}

_{* | Simone Ribero}

_{| Stefano Taddei}

_|

Veronique Bataille

_{| Claire J. Steves}

This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

© 2018 The Authors. Pigment Cell & Melanoma Research Published by John Wiley & Sons Ltd

*These authors equally contributed to the manuscript.

1_{Department of Twin Research & Genetic}

Epidemiology, King’s College London, London, UK

2_{Department of Clinical and Experimental}

Medicine, University of Pisa, Pisa, Italy

3_{First Department of Cardiology,}

Hippokration Hospital, University of Athens, Athens, Greece

4_{Department of Ageing and Health, Guys}

and St, Thomas’s NHS Foundation Trust, London, UK

5_{Department of Medical Sciences,}

Dermatologic Clinic, University of Turin, Turin, Italy

Correspondence

Claire Steves, Department of Twin Research & Genetic Epidemiology, King’s College London, St Thomas’ Hospital Campus, 3rd & 4th Floor South Wing Block D, Westminster Bridge Road, London SE1 7EH, UK. Email: claire.j.steves@kcl.ac.uk

Funding information

Wellcome Trust; European Community’s Seventh Framework Programme, Grant/ Award Number: FP7/2007-2013; National Institute for Health Research (NIHR)-funded BioResource; Clinical Research Facility and Biomedical Research Centre; St Thomas’ NHS Foundation Trust; King’s College London; Chronic Disease Research Foundation; National Institute for Health Research and Health Education England

Abstract

The presence of a skin–brain connection whereby alterations in the skin can inform on mechanisms underlying neurodegenerative diseases is increasingly recognized. In this study, we used a discovery (n = 321) and replication (n = 147) sample from the Twins UK population to test the association between naevus count and memory function, and its mediation by telomeres. Memory function was assessed in 1999 and 2009 using the paired associates learning test (PAL), while naevus count and leuco-cyte telomere length (LTL, assessed by the terminal restriction fragment assay) were measured once. Higher baseline naevus count was significantly associated with fewer errors at the baseline and follow- up PAL, as well as with change in PAL score over 10 years. This association was significantly attenuated after adjustment for LTL. The significant association between naevus count and PAL score was reproduced in the replication sample. These findings suggest that melanocytes might be used as model system to study the biological ageing pathways involved in neurodegeneration.

K E Y W O R D S

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MASI etAl.

1 | INTRODUCTION

The presence of a skin–brain connection, so that alterations de-tected on the skin might inform on specific neurogenerative pro-cesses underlying Parkinson’s disease and Alzheimer’s disease (AD), is attracting increasing interest (Clos, Kayed, & Lasagna- Reeves, 2012). Indeed, the biological processes underlying neurodegenera-tive diseases are complex, and the limited availability of suitable neuronal models for neurodegenerative research has hindered the understanding of the biological pathways involved in the disease ini-tiation and evolution, as well as the identification of potential thera-peutic targets.

Several reports have documented deficits of episodic memory in subjects who will develop AD or other neuropsychiatric disor-ders prior to diagnostically significant cognitive changes. Using data collected within the Twins UK study, which is a volunteer twin registry representative to the broader UK population regarding disease- related and lifestyle characteristics (Andrew et al., 2001), our group has recently reported an association between short leu-cocyte telomere length (LTL) and impaired episodic memory (Valdes et al., 2010). This association remained significant after adjustment for chronological age, suggesting that LTL might contribute to char-acterize the insidious transition from normal ageing to dementia, identifying people within the general population at increased risk of neuropsychiatric disorders because of a faster evolution of biologi-cal ageing.

Neurons are long- living postmitotic cells, which share several features with epidermal melanocytes, including a common embry-ological origins (Slominski, Tobin, Shibahara, & Wortsman, 2004). Similarly to episodic memory, total body naevus count declines with ageing and we previously documented that shorter LTL is associated with lower number of naevi, even after adjustment for chronological age (Bataille et al., 2007).

This evidence suggests that shared biological ageing pathways, captured by the measure of LTL, might influence both the evolution of neurodegenerative diseases underlying AD and the replicative potential within a naevus clone.

Based on this background, we used two independent samples from the Twins UK population to explore the relationship between

naevus count and episodic memory, as well as whether this asso-ciation could be explained, at least in part, by biological ageing (as assessed by LTL). The first (discovery) sample included 321 par-ticipants with measures of episodic memory function available in 1999 and 2009, and whole body naevus count assessed at base-line (Table 1). In this sample, 187 participants also had measures of LTL. The second (replication) sample included 147 participants who underwent at least one memory function and naevus count assessment between 2006 and 2016 (Table 1). Both samples in-cluded participants free of overt dementia or cognitive impair-ment. A naevus was defined as a melanocytic lesion ≥2 mm in diameter to avoid any confusion with ephelides, and the protocol used for whole body naevus counting has been validated in the previous studies (Bataille et al., 1996, 1998). The paired associates learning (PAL) test (adjusted errors at eight boxes), which is part of the computerized CANTAB cognitive test battery (Robbins et al., 1994), was used to assess episodic memory function. This test was selected as previous reports documented its capacity to detect memory changes predictive of AD and to provide a reliable esti-mate of memory changes in follow- up studies (Barnett, Blackwell, Sahakian, & Robbins, 2016). Characteristics of the test and the method used for its administration were described in Steves et al.

Significance

The results of our study suggest that shared biological age-ing pathways might control melanocyte biology and the process of neurodegeneration leading to memory decline. The limited availability of suitable neuronal models to study the biological alterations underlying neurodegenera-tive diseases has precluded identification of potential ther-apeutic targets. Our results suggest that melanocytes and neurons might preserve common biological regulations in postnatal life and support the use of readily available mel-anocytes from the skin to shed light on the complex biol-ogy underlying neurodegenerative diseases.

Samples Variable N Mean Std. Dev.

Discovery Age (years) 276 53 7

Paired Associates Learning 1999 (total errors)

315 22 20

Paired Associates Learning 2009 (total errors)

321 22 22

Leucocyte telomere length (kB pair) 187 7.003 0.581

Whole body naevus count (n) 297 31 38

Replication Age (years) 145 67 6

Paired Associates Learning (total error adjusted)

145 17 15

Whole body naevus count (n) 145 36 36

TA B L E   1   Clinical characteristics of the

study population in the discovery and replication samples

(Steves, Jackson, & Spector, 2013). Mean leucocyte terminal re-striction fragment length was used as a measure of LTL and as-sessed by the Southern blot method, as previously described (Bataille et al., 2007). Ethics Committee approval for the Twins UK study was obtained from the Guy’s and St Thomas Hospital NHS Trust, London. Subjects were not aware of the hypotheses being tested in this study at the time of recruitment.

In the discovery sample, change in PAL score for the periods 1999- 2009 conditional on earlier PAL score was calculated by re-gressing the PAL follow- up score on the earlier PAL measure, saving and standardizing the residuals. Subsequently, we implemented a series of generalized estimating equations (GEE) to fit population- averaged panel- data (i.e., pairs of twins) models with unstructured within- group correlation for the association of (a) baseline naevus count with memory function both at baseline and follow- up, (b) baseline naevus count and changes in episodic memory, (c) LTL and naevus count at baseline and d) LTL and episodic memory. Normal distribution of the dependent continuous variables was graphically inspected with histograms and distributional plots (i.e., percentile– percentile plots). Variables that deviated from normality were trans-formed with the natural logarithm before entering the GEE analysis. Results from the GEE analysis are presented as coefficients (β) and 95% confidence intervals (CI). To explore the proportion of the asso-ciation between baseline naevus count and change in PAL explained by chronological or biological age, we included age and LTL, sepa-rately and in combination, in the models exploring the relationship

between baseline naevus count and PAL residuals. The GEE analysis for the association between naevus count and PAL score was re-peated in the replication sample. The Stata 13 statistical package was used for all analyses. We deemed statistical significance at α = 0.05.

Participants with higher naevus count had a better episodic memory (making fewer errors at the PAL) both at the baseline (β = −0.209; 95% CI - 0.384, - 0.034; p = 0.019) and follow- up (β = −0.401; 95% CI −0.617, −0.186; p < 0.001) assessments. Naevus count was also related with LTL, so that people with higher naevus count had longer LTL (β = 0.280; 95% CI 0.011, 0.549; p = 0.041). In turn, LTL was associated with the performance at the PAL test (β = −0.047; 95% CI −0.075, −0.019; p < 0.001). All these associa-tions remained significant after adjustment for chronological age. People with higher naevus count at baseline had a lower memory decline during follow- up (β = 0.192; 95% CI 0.075, 0.309; p = 0.001) (Table 2). Importantly, while adjustment for age did not affect this association (β = 0.216; 95% CI 0.018, 0.414; p = 0.032), further ad-justment for LTL substantially reduced the strength of the asso-ciation between naevus count and change in PAL (β = 0.095; 95% CI −0.168, 0.358; p = 0.478) (Table 3a). In this model, LTL was sig-nificantly associated with change in PAL (β = 0.495; 95% CI 0.076, 0.914; p = 0.020), while chronological age was not (β = −0.017; 95% CI −0.049, 0.014; p = 0.267).

Following the same statistical approach, but with PAL results log transformed as non- normally distributed, the association between

TA B L E   2   Unadjusted associations of naevus count at baseline with (a) paired associates learning test (PAL) results at the same

assessment, (b) paired associates learning test (PAL) results at follow- up, (c) change in paired associates learning test (PAL) and iv) LTL in the discovery sample

PAL Baseline (1999) PAL at follow- up (2009) Change in PAL Telomeres (TRF)

Coef (95% CI) p Coef (95% CI) p Coef (95% CI) p Coef (95% CI) p

Whole body

naevus count −0.209 (−0.384, −0.034) 0.019 −0.401 (−0.617, −0.186) <0.001 0.192 (0.075, 0.309) 0.001 0.280 (0.011, 0.549) 0.041

Note. Associations were established using generalized estimating equations.

TA B L E   3   Unadjusted and multiadjusted association between (a) baseline naevus count and changes in PAL in the discovery sample, and

(b) naevus count and PAL test in the replication sample

Change in PAL

Unadjusted Adjusted for age Adjusted for age + telomeres (TRF)

Coef (95% CI) p Coef (95% CI) p Coef (95% CI) p

(a) Discovery sample

Whole body naevus count

0.192 (0.075; 0.309) 0.001 0.216 (0.018; 0.414) 0.032 0.095 (−0.168; 0.358) 0.478

Log (PAL Total Error Adj)

(b) Replication sample Coef (95% CI) p Coef (95% CI) p

Whole body naevus count

−0.003 (−0.006, −0.0005) 0.023 −0.004 (−0.007, −0.001) 0.017

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MASI etAl.

naevus count and PAL score was confirmed using the cross- sectional data available in the replication sample (β = −0.003; 95% CI −0.006, −0.0005; p = 0.023). Similar to the results obtained in the discov-ery sample, this association was unaffected by adjustment for age (β = −0.004; 95% CI −0.007, −0.001; p = 0.017) (Table 3b). The lim-ited number of survey participants with telomeres, naevus count and cognitive data in the replication sample did not enable replication of the LTL mediation analysis.

These results show, for the first time, an association between cross- sectional measures of naevus count and episodic memory, as well as that baseline naevus count can predict decline in episodic memory over 10- year follow- up. They also document that these as-sociations are likely to be mediated by pathways regulating biolog-ical ageing. Our data support the hypothesis that shared biologbiolog-ical ageing pathways influence the process of neurodegeneration asso-ciated with decline in episodic memory as well as melanocyte regen-erative capacities.

Decline in episodic memory is commonly observed after 30–35 years of age, and its rapid impairment has been linked not only with the risk of AD but also with other neuropsychiatric disor-ders characterized by reduction in hippocampal volume (Dickerson & Eichenbaum, 2010; Kuhn & Gallinat, 2014; Van Petten, 2004), in-cluding bipolar disorder, major depressive disorder and schizophre-nia (Bora, Harrison, Yucel, & Pantelis, 2013; Bora, Yucel, & Pantelis, 2009; Bourne et al., 2013; Lim et al., 2013; Szoke et al., 2008). As telomere length controls cellular replication capacities and path-ways of cellular senescence/degeneration, an altered telomere dy-namic might account for a faster hippocampal volume loss which, in turn, might represent the morphological substrate accounting for the faster impairment in episodic memory observed in subjects with shorter LTL in this and previous studies (Valdes et al., 2010). In keeping with this hypothesis, several reports described associations between hippocampal volume and LTL (King et al., 2014; Nilsonne, Tamm, Mansson, Akerstedt, & Lekander, 2015). Like episodic mem-ory, loss and degeneration of skin melanocytes determine a progres-sive decline in naevus count from the third decade of life and we previously documented that a lower total body naevus count is asso-ciated with shorter LTL (Bataille et al., 2007). Taken together, this ev-idence suggests that the rate of decline in naevus count might help identification of people within the general population with altered regulation of biological ageing pathways, thus with a greater risk of hippocampal degeneration, episodic memory decline and, ultimately, neurodegenerative diseases. This is confirmed by genetic studies showing that single nucleotide variants or epigenetic modifications in the region of TERT are associated with naevus count (Roos et al., 2017) and the risk of Alzheimer’s disease (Zhan et al., 2015).

Our study has several strengths. The availability of robust memory measures assessed at two different time points 10 years apart reduces the risk of learning effects, often complicating the interpretation of changes in cognitive function observed in longi-tudinal studies. Previous reports have validated the PAL tests for the assessment of episodic memory deficits, showing its ability to detect early memory changes predictive of AD risk. LTL was

measured using terminal restriction fragment, which is currently considered the gold standard method for LTL assay. Finally, the work previously published by our group on the relationship of LTL with episodic memory as well as with naevus count increases the robustness of our results. Among limitations, while the association between naevus count and memory function was replicated in two independent samples, the size of both samples was relatively small. Also, while several reports have now demonstrated that telomere length is highly synchronized between different cells and tissues at any age (Butler et al., 1998), telomeres were measured in peripheral leucocytes and not directly on melanocytes and/or neurons.

In conclusion, the inverse association between naevus count and risk of episodic memory decline observed in our study suggests that a faster age- related decline in naevus count might help identifica-tion of people with faster evoluidentifica-tion of biological ageing, and thus at greater risk of neuropsychiatric disorders. Also, our findings suggest that peripheral melanocytes could maintain common biological reg-ulation with neurons in postnatal life, at least for pathways influenc-ing the progression of biological ageinfluenc-ing. Consequently, clarification of the mechanisms involved in the control of biological ageing of peripheral melanocytes might provide valuable information on the potential pathways involved in neurodegeneration and leading to memory decline.

ACKNOWLEDGEMENTS

TwinsUK received funding from the Wellcome Trust (WT086904MF & WT081878MA); European Community’s Seventh Framework Programme (FP7/2007- 2013), the National Institute for Health Research (NIHR)- funded BioResource; Clinical Research Facility and Biomedical Research Centre based at Guy’s and St Thomas’ NHS Foundation Trust in partnership with King’s College London. CJS was funded under a grant from the Chronic Disease Research Foundation (CDRF). SM was funded by National Institute for Health Research and Health Education England through a Clinical Lectureship.

ORCID

Stefano Masi http://orcid.org/0000-0002-7591-3686

Claire J. Steves http://orcid.org/0000-0002-4910-0489

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How to cite this article: Masi S, Georgiopoulos G, Ribero S,

Taddei S, Bataille V, Steves CJ. The relationship between naevus count, memory function and telomere length in the Twins UK cohort. Pigment Cell Melanoma Res. 2018;31:720– 724. https://doi.org/10.1111/pcmr.12722